| 1. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 2. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 3. |
- Klareskog, L., et al.
(författare)
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The importance of differences : On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis
- 2020
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 287:5, s. 514-533
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Forskningsöversikt (refereegranskat)abstract
- The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.
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| 4. |
- Nurul-Aain, AF, et al.
(författare)
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ASSOCIATIONS BETWEEN HLA-DRB1 SHARED EPITOPES ALLELES AND ANTI-RA33 ANTIBODIES IN DIFFERENT SUBSETS OF RHEUMATOID ARTHRITIS IN MALAYSIAN POPULATION
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 408-408
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The mechanisms affecting anti-RA33 antibody’s involvement in RA pathogenesis is still unclear. Refining our understanding of anti-RA33’s role in RA in relation to known RA-associated genes and serological elements is needed.Objectives:We investigated the relationship between RA-associated HLA-DRB1 epitope (SE) allele and presence of anti-RA33 antibodies in different serological subsets of rheumatoid arthritis in a Malaysian population.Methods:Serum samples from 550 RA cases comprising seronegative (negative for anti-CCP2, IgG and IgM, n=250), seropositive (triple-autoantibody positive, n=150), singular anti-CCP2 positive (n=100), and double RF positive RA (n=50) were chosen from the Malaysian Epidemiological Investigations of RA (MyEIRA) case-control study. Three hundred MyEIRA population controls were used for comparison. All serum samples were assayed using a commercial anti-RA33 ELISA kit. All genetic samples were genotyped for four-digit HLA-DRB1 alleles using the PCR-SSO method on Luminex platform.Results:The proportions of anti-RA33 positive was 20.9% in all RA cases (i.e. 34% in RF only positive RA; 25% in seropositive RA; 18% in seronegative RA and 18% in anti-CCP2 only positive RA). The HLA-DRB1 shared epitope alleles were significantly associated with anti-RA33 positive in the seropositive RA subgroup (OR=6.9, 95% CI 1.4-34.8; p=0.02). We observed significant association between anti-RA33 negative and HLA-DRB1 SE alleles among the seropositive RA patients (OR=4.5, 95% CI 2.8-7.2; p<0.001) and among CCP only positive RA (OR=4.4; 95% CI 2.6-7.4; p<0.01). No association was observed between anti-RA33 status and HLA-DRB1 SE alleles in seronegative RA and RF only positive RA.Conclusion:The HLA-DRB1 SE alleles increased the risk of seropositive and CCP only positive RA independent of anti-RA33 positivity.References:[1]Boeters, Debbie M et al. “The 2010 ACR/EULAR criteria are not sufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: Results from the Leiden-EAC and ESPOIR cohorts.” Seminars in arthritis and rheumatism vol. 47,2 (2017): 170-174.[2]de Brito Rocha, Sara et al. “Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis.” Advances in rheumatology (London, England) vol. 59,1 2. 17 Jan. 2019.Acknowledgements:The authors would like to thank the Director General of Health, Ministry of Health Malaysia for supporting this study. The authors are also indebted to participants for their kind participation. This study was financially supported by the Ministry of Health, Malaysia (JPP-IMR 08-012).Disclosure of Interests:None declared
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| 5. |
- Sabrina, MRNA, et al.
(författare)
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CHANGES OF RF ISOTYPE PROFILE IN PATIENTS WITH RHEUSMATOID ARTHRITIS: DATA FROM 10 YEARS FOLLOW-UP STUDY
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 459-460
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Presence of autoantibodies such as anti-cyclic citrullinated peptide (anti-CCP2) and rheumatoid factor (RF) is of considerable diagnostic and prognostic value in patients with rheumatoid arthritis (RA). Limited data are available for autoantibody profile changes over time in patients with RA.Objectives:Thus, we compared the presence of anti-CCP2 and different RF isotypes in individual RA patients at baseline and during 10 years follow-up.Methods:A total of 320 RA patients from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case-control study was included in this study. The presence of anti-CCP2, IgM RF, IgG RF, and IgA RF at baseline and at later time point (±10 years) were determined using enzyme-linked immunosorbent assays, with identical techniques in paired samples. Seropositive RA is defined by the presence of at least one autoantibody, whilst seronegative RA is defined by the absence of all investigated autoantibodies.Results:The proportion of seropositive RA were higher for the follow-up samples (n=263, 82.2%) as compared to the baseline samples (n=251, 78.4%). Among the baseline samples, 105 (41.8%) were positive for anti-CCP2 and all RF isotypes. Of these individuals, 85 (81.0%) remained positive for all antibodies at the follow-up, while 20 (19.0%) lost one or more RF isotypes (4 IgM RF, 19 IgG RF and 13 IgA RF). Interestingly, 14 (5.6%) RA patients who were seropositive at baseline became totally seronegative after follow-up. Among the 69 patients seronegative at baseline, 26 (37.7%) acquired one or more autoantibodies at follow-up (14 IgM RF, 2 IgG RF, 9 IgA RF and 8 anti-CCP2) (Figure 1).Conclusion:Anti-CCP2 present at baseline usually remained at follow-up. Among Malaysian RA patients, changes in status were mainly found for RF of all isotypes.References:[1]Barra, Lillian et al. “Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review.” Rheumatology (Oxford, England) vol. 50,2 (2011): 311-6.[2]van Delft, Myrthe A M, and Tom W J Huizinga. “An overview of autoantibodies in rheumatoid arthritis.” Journal of autoimmunity vol. 110 (2020): 102392.Figure 1.Comparison of serum autoantibody profile in rheumatoid arthritis patients during baseline enrolment and 10 years follow-up.Acknowledgements:The authors would like to thank the Director General of Health, Ministry of Health Malaysia for supporting this study. The authors are also indebted to participants for their kind participation. This study was financially supported by the Ministry of Health, Malaysia (JPP-IMR 08-012; 18-051).Disclosure of Interests:None declared
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| 6. |
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| 7. |
- Tan, LK, et al.
(författare)
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EXPOSURE TO DENGUE INFECTION DO NOT RAISE RISK OF RHEUMATOID ARTHRITIS: FINDINGS FROM THE MALAYSIAN EPIDEMIOLOGICAL INVESTIGATION OF RHEUMATOID ARTHRITIS (MYEIRA) CASE-CONTROL STUDY
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 53-53
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Dengue infection is associated with joints pain mimicking disease onset symptom of rheumatoid arthritis (RA). However, there is lack of epidemiological studies on exposure to dengue infection and risk of future RA.Objectives:We investigated the relationship between exposure to dengue infection and risk of developing different subsets of RA, defined by the presence of anti-citrullinated peptide antibody (ACPA) in the multi-ethnic Malaysian population.Methods:Serum samples from 1,235 RA cases (i.e. 516 Malay, 254 Chinese, 405 Indians and 60 others/mixed-ethnicity) and 1,624 epidemiological matched population-based controls (i.e. 1,023 Malay, 208 Chinese, 297 Indians and 96 others/mixed-ethnicity) were assayed for presence of dengue IgG antibody using World Health Organization recommended ELISA kits. Positive results of dengue IgG antibodies indicates previous exposure to dengue infection(s). We performed chi-square and Mann-Whitney U analysis to determine the association of ever-exposed dengue infection with ACPA-positive/ACPA-negative RA and to investigate the antibody frequency and levels among the studied populations.Results:We observed high occurrence of dengue IgG antibody in the overall RA cases (79.7%) and matched controls (77.3%), with no significant differences detected between the ACPA subsets of RA. Ethnicity stratification analysis revealed a decrease risk of developing ACPA-positive RA in the Indian patients with positive dengue IgG antibody (OR=0.59, 95% CI=0.37-0.94, p=0.03), and in particular patients with elevated level of dengue IgG antibody (OR=0.44, 95% CI=0.25-0.78, p<0.05). On the other hand, the significant decrease mean levels of dengue IgG antibody were observed in the ACPA-positive RA subset for all three major ethnic groups (i.e. Malay, p<0.0001, Chinese, p<0.01 and Indian<0.05) (Figure 1). No association was observed between presence of dengue IgG antibody and ACPA-negative RA subset.Figure 1.Comparison of mean dengue IgG antibody level between ever-exposed dengue infection RA cases, stratified by ACPA status. Comparison of median dengue IgG antibody level between the ever-exposed dengue infection ACPA-positive RA and normal controls in the four ethnic groups. The red line indicates the mean level of dengue IgG antibody levelConclusion:Our findings demonstrated that exposure to dengue infection do not increase the risk of developing future RA in the multi-ethnic Malaysian population. The inverse associations observed in the Indian ethnic group are in line with the other studies investigating exposure to viral infection and risk of RA.References:[1]Sherina et al (2017) Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Arthritis Research & Therapy 2017, 19:2169[2]Gissel García et. al. (2011) Long-term persistence of clinical symptoms in dengue-infected persons and its association with immunological disorders. International Journal of Infectious Diseases 15 (2011) e38–e43Acknowledgements:The authors would like to thank the Director General of Health, Ministry of Health Malaysia for supporting this study. The authors are also indebted to participants for their kind participation. This study was financially supported by the Ministry of Health, Malaysia (JPP-IMR 17-025) and the short-term research grant by UniKL RCMP (str16037).Disclosure of Interests:None declared
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| 8. |
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| 9. |
- Tang, BW, et al.
(författare)
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Reply
- 2021
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 73:10, s. 1944-1945
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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